tbuckley/cabot-search huggingface dataset:
Metabolomic profiles predict individual multidisease outcomes
Authors: Thore Buergel, Jakob Steinfeldt, Greg Ruyoga, Maik Pietzner, Daniele Bizzarri, Dina Vojinovic, Julius Upmeier zu Belzen, Lukas Loock, Paul Kittner, Lara Christmann, Noah Hollmann, Henrik Strangalies, Jana M. Braunger, Benjamin Wild, Scott T. Chiesa, Joachim Spranger, Fabian Klostermann, Erik B. van den Akker, Stella Trompet, Simon P. Mooijaart, Naveed Sattar, J. Wouter Jukema, Birgit Lavrijssen, Maryam Kavousi, Mohsen Ghanbari, Mohammad A. Ikram, Eline Slagboom, Mika Kivimaki, Claudia Langenberg, John Deanfield, Roland Eils, Ulf Landmesser
Journal: Nature Medicine (2022)

Abstract Risk stratification is critical for the early identification of high-risk individuals and disease prevention. Here we explored the potential of nuclear magnetic resonance (NMR) spectroscopy-derived metabolomic profiles to inform on multidisease risk beyond conventional clinical predictors for the onset of 24 common conditions, including metabolic, vascular, respiratory, musculoskeletal and neurological diseases and cancers. Specifically, we trained a neural network to learn disease-specific metabolomic states from 168 circulating metabolic markers measured in 117,981 participants with ~1.4 million person-years of follow-up from the UK Biobank and validated the model in four independent cohorts. We found metabolomic states to be associated with incident event rates in all the investigated conditions, except breast cancer. For 10-year outcome prediction for 15 endpoints, with and without established metabolic contribution, a combination of age and sex and the metabolomic state equaled or outperformed established predictors. Moreover, metabolomic state added predictive information over comprehensive clinical variables for eight common diseases, including type 2 diabetes, dementia and heart failure. Decision curve analyses showed that predictive improvements translated into clinical utility for a wide range of potential decision thresholds. Taken together, our study demonstrates both the potential and limitations of NMR-derived metabolomic profiles as a multidisease assay to inform on the risk of many common diseases simultaneously.
Association of QTc Formula With the Clinical Management of Patients With Cancer
Authors: Daniel R. Richardson, P. Christopher Parish, Xianming Tan, Julia Fabricio, Cami L. Andreini, Charles H. Hicks, Brian C. Jensen, Benyam Muluneh, Joshua F. Zeidner
Journal: JAMA Oncology (2022)

Monitoring of the corrected QT interval (QTc) for patients with cancer receiving chemotherapy is not standardized. Selection of QTc formula may be associated with adverse event grading and chemotherapy delivery.To describe the association of QTc formula selection with adverse event grading and chemotherapy delivery.This retrospective observational cohort study used data from January 2010 to April 2020 and included adult patients seen at the University of North Carolina Cancer Hospital who had an electrocardiogram (ECG) performed.Adjusted QTc using the Bazett, Fridericia, and Framingham formulae.The main outcome was QTc prolongation using the Common Terminology Criteria for Adverse Events (CTCAE). Consistency between formulae was evaluated. Subsequently, appropriateness of clinical management due to prolonged QTc was assessed for a subset of patients being treated with chemotherapy agents associated with a prolonged QT interval. We hypothesized that use of the Bazett formula would be associated with higher rates of QTc prolongation and inappropriate modifications to chemotherapy.A total of 19 955 ECGs from 6881 adult patients (3055 [44.4%] women, 3826 [55.6%] men; median [IQR] age at first ECG, 60 [47-68] years) were analyzed. The percentage of ECGs with grade 3 QTc prolongation differed by formula (all patients: Framingham, 1.8%; Fridericia, 2.8%; and Bazett, 9.0%; patients receiving QT-prolonging chemotherapy [2340 ECGs]: Framingham, 2.7%; Fridericia, 4.5%; and Bazett, 12.5%). The Bazett formula resulted in a median QTc value 26.4 milliseconds higher than Fridericia and 27.8 milliseconds higher than Framingham. Of the 1786 ECGs classified as grade 3 by Bazett, 1446 (81.0%) were grade 2 or less by either Fridericia or Framingham. A total of 5 of 28 (17.9%) evaluated clinical changes associated with prolonged QTc were deemed inappropriate when using either Fridericia or Framingham formula.Findings of this cohort study suggest that the Bazett formula resulted in higher QTc values associated with a 3-fold increase in grade 3 CTCAE toxic effects compared with other common formulae. Use of the Bazett formula likely was associated with inappropriate changes in clinical management. These data support the use of a standard QTc formula (such as Fridericia or Framingham) for QTc correction in oncology.
Use and Reporting of Patient-Reported Outcomes in Trials of Palliative Radiotherapy
Authors: Alexander Fabian, Justus Domschikowski, Anne Letsch, Claudia Schmalz, Sandra Freitag-Wolf, Juergen Dunst, David Krug
Journal: JAMA Network Open (2022)

Importance Approximately 50% of all patients with cancer have an indication for radiotherapy, and approximately 50% of radiotherapy is delivered with palliative intent, with the aim of alleviating symptoms. Symptoms are best assessed by patient-reported outcomes (PROs), yet their reliable interpretation requires adequate reporting in publications. Objective To investigate the use and reporting of PROs in clinical trials of palliative radiotherapy. Evidence Review This preregistered systematic review searched PubMed/Medline, EMBASE, and the Cochrane Center Register of Controlled Trials for clinical trials of palliative radiotherapy published from 1990 to 2020. Key eligibility criteria were palliative setting, palliative radiotherapy as treatment modality, and clinical trial design (per National Institutes of Health definition). Two authors independently assessed eligibility. Trial characteristics were extracted and standard of PRO reporting was assessed in adherence to the Consolidated Standards of Reporting Trials (CONSORT) PRO extension. The association of the year of publication with the use of PROs was assessed by logistic regression. Factors associated with higher CONSORT-PRO adherence were analyzed by multiple regression. This study is reported following the PRISMA guidelines. Findings Among 7377 records screened, 225 published clinical trials representing 24 281 patients were eligible. Of these, 45 trials (20%) used a PRO as a primary end point and 71 trials (31%) used a PRO as a secondary end point. The most prevalent PRO measures were the Numeric Rating Scale/Visual Analogue Scale (38 trials), European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire C30 (32 trials), and trial-specific unvalidated measures (25 trials). A more recent year of publication was significantly associated with a higher chance of PROs as a secondary end point (odds ratio [OR], 1.04 [95% CI, 1.00-1.07]; P = .03) but not as primary end point. Adherence to CONSORT-PRO was poor or moderate for most items. Mean (SD) adherence to the extension adherence score was 46.2% (19.6%) for trials with PROs as primary end point and 31.8% (19.8%) for trials with PROs as a secondary end point. PROs as a primary end point (regression coefficient, 9.755 [95% CI, 2.270-17.240]; P = .01), brachytherapy as radiotherapy modality (regression coefficient, 16.795 [95% CI, 5.840-27.751]; P = .003), and larger sample size (regression coefficient, 0.028 [95% CI, 0.006-0.049]; P = .01) were significantly associated with better PRO reporting per extension adherence score. Conclusions and Relevance In this systematic review of palliative radiotherapy trials, the use and reporting of PROs had room for improvement for future trials, preferably with PROs as a primary end point.
SAIGE-GENE+ improves the efficiency and accuracy of set-based rare variant association tests
Authors: Wei Zhou, Wenjian Bi, Zhangchen Zhao, Kushal K. Dey, Karthik A. Jagadeesh, Konrad J. Karczewski, Mark J. Daly, Benjamin M. Neale, Seunggeun Lee
Journal: Nature Genetics (2022)

Abstract Several biobanks, including UK Biobank (UKBB), are generating large-scale sequencing data. An existing method, SAIGE-GENE, performs well when testing variants with minor allele frequency (MAF) ≤ 1%, but inflation is observed in variance component set-based tests when restricting to variants with MAF ≤ 0.1% or 0.01%. Here, we propose SAIGE-GENE+ with greatly improved type I error control and computational efficiency to facilitate rare variant tests in large-scale data. We further show that incorporating multiple MAF cutoffs and functional annotations can improve power and thus uncover new gene–phenotype associations. In the analysis of UKBB whole exome sequencing data for 30 quantitative and 141 binary traits, SAIGE-GENE+ identified 551 gene–phenotype associations.
Ann Robinson’s research reviews—22 September 2022
Authors: Ann Robinson
Journal: BMJ (2022)

Buckling under pressureChildren break their wrists with alarming ease and frequency.The commonest type of fracture in children is a torus (from the Latin for protuberance) or buckle fracture, in which the soft, compressible radius and ulna bend or crack under the impact of a fall but don't break into the cortex.Approaches to treatment differ, and this large multicentre UK trial found that treatment with a bandage and immediate discharge was as safe and effective as rigid immobilisation (using a wrist splint in 97% of cases and plaster cast in 3%) and routine follow-up regardless of the age of the child.No one needed surgery or fracture manipulation.The bandage group used more analgesia in the first 24 hours, but, overall, the rate of complications, pain, return to school, and self reported function scores didn't differ between the two groups at six weeks after the injury.These results reinforce a Cochrane review confirming that pain and recovery are equivalent regardless of treatment.In this study, 10% of younger children (4-7 year olds) and 6% of older ones (8-15 year olds) changed treatment in the first three days, mostly from bandage to rigid immobilisation and primarily because of pain.This may reflect the fact that parents and carers often regard a splint or cast as better than a bandage and clinicians may bow to, or share, that belief-despite this strong evidence to the contrary.
Compartment-specific mutational landscape of clonal hematopoiesis
Authors: Luise Hartmann, Judith S. Hecker, Maja Rothenberg-Thurley, Jennifer Rivière, Madlen Jentzsch, Bianka Ksienzyk, Michèle C. Buck, Mark van der Garde, Luise Fischer, Susann Winter, Martina Rauner, Elena Tsourdi, Heike Weidner, Katja Sockel, Marie Schneider, Anne S. Kubasch, Martin Nolde, Dominikus Hausmann, Jörg Lützner, Szymon Goralski, Florian Bassermann, Karsten Spiekermann, Lorenz C. Hofbauer, Sebastian Schwind, Uwe Platzbecker, Katharina S. Götze, Klaus H. Metzeler
Journal: Leukemia (2022)

Clonal hematopoiesis (CH) is characterized by somatic mutations in blood cells of individuals without hematologic disease. While the mutational landscape of CH in peripheral blood (PB) has been well characterized, detailed analyses addressing its spatial and cellular distribution in the bone marrow (BM) compartment are sparse. We studied CH driver mutations in healthy individuals (n = 261) across different anatomical and cellular compartments. Variant allele frequencies were higher in BM than PB and positively correlated with the number of driver variants, yet remained stable during a median of 12 months of follow-up. In CH carriers undergoing simultaneous bilateral hip replacement, we detected ASXL1-mutant clones in one anatomical location but not the contralateral side, indicating intra-patient spatial heterogeneity. Analyses of lineage involvement in ASXL1-mutated CH showed enriched clonality in BM stem and myeloid progenitor cells, while lymphocytes were particularly involved in individuals carrying the c.1934dupG variant, indicating different ASXL1 mutations may have distinct lineage distribution patterns. Patients with overt myeloid malignancies showed higher mutation numbers and allele frequencies and a shifting mutation landscape, notably characterized by increasing prevalence of DNMT3A codon R882 variants. Collectively, our data provide novel insights into the genetics, evolution, and spatial and lineage-specific BM involvement of CH.
NUDT21 limits CD19 levels through alternative mRNA polyadenylation in B cell acute lymphoblastic leukemia
Authors: Matthew T. Witkowski, Soobeom Lee, Eric Wang, Anna K. Lee, Alexis Talbot, Chao Ma, Nikolaos Tsopoulidis, Justin Brumbaugh, Yaqi Zhao, Kathryn G. Roberts, Simon J. Hogg, Sofia Nomikou, Yohana E. Ghebrechristos, Palaniraja Thandapani, Charles G. Mullighan, Konrad Hochedlinger, Weiqiang Chen, Omar Abdel-Wahab, Justin Eyquem, Iannis Aifantis
Journal: Nature Immunology (2022)
Meniscal procedures are not increased with delayed ACL reconstruction and rehabilitation: results from a randomised controlled trial
Authors: Sabine J A van der Graaff, Max Reijman, Eline M van Es, Sita M A Bierma-Zeinstra, Jan A N Verhaar, Duncan E Meuffels
Journal: British Journal of Sports Medicine (2022)

Objective To assess whether initial non-operative treatment of anterior cruciate ligament (ACL) ruptures with optional delayed ACL reconstruction leads to more meniscal procedures compared with early ACL reconstruction during the 2-year follow-up. Methods We compared the number of meniscal procedures of 167 patients with an ACL rupture, who either received early ACL reconstruction (n=85) or rehabilitation therapy plus optional delayed ACL reconstruction (n=82), participating in the Conservative vs Operative Methods for Patients with ACL Rupture Evaluation trial. Patients were aged 18 to 65 years (mean 31.3, SD 10.5), 60% male sex (n=100). We evaluated the presence and location of meniscal tears by baseline MRI. We analysed and compared how many patients per randomisation group had a meniscal procedure during follow-up in the ACL injured knee, adjusted for sex, body mass index, age group and orthopaedic surgeon. Results At baseline, 41% of the entire study population (69/167 patients) had a meniscal tear on MRI. During the 2-year follow-up, 25 patients randomised to early ACL reconstruction (29%, 25/85 patients) had a meniscal procedure, compared with 17 patients randomised to rehabilitation plus optional delayed reconstruction (21%, 17/82 patients) (risk ratio 0.67 with 95% CI 0.40 to 1.12, p=0.12). Of these patients who received early ACL reconstruction (n=82) and patients that received delayed ACL reconstruction (n=41), 5% of the patients had an additional isolated meniscal procedure after ACL reconstruction. In patients who received no ACL reconstruction (n=41), 10% (n=4) had an isolated surgical procedure for a meniscal tear during the 2-year follow-up period. Conclusion Initial non-surgical treatment of ACL ruptures followed by optional delayed ACL reconstruction does not lead to a higher number of meniscal procedures compared with early ACL reconstruction over a 2-year follow-up period. Trial registration number NL 2618.
Transforming Management of Opioid Use Disorder with Universal Treatment
Authors: Rahul Gupta, Rachel L. Levine, Javier A. Cepeda, David R. Holtgrave
Journal: New England Journal of Medicine (2022)

Interview with Dr. Rahul Gupta on strategies for promoting use of medication for opioid use disorder. (09:28)Download Barriers at multiple levels impede the use of evidence-based medication for opioid use disorder. Actions by clinicians, health care systems, and policymakers could substantially expand treatment access.
Identifying latent classes of Relative Energy Deficiency in Sport (RED-S) consequences in a sample of collegiate female cross country runners
Authors: Traci Lyn Carson, Brady T West, Kendrin Sonneville, Ronald F Zernicke, Philippa Clarke, Sioban Harlow, Carrie Karvonen-Gutierrez
Journal: British Journal of Sports Medicine (2022)

The purpose of this study was to identify patterns of clustering of the 10 health consequences identified in the Relative Energy Deficiency in Sport (RED-S) framework among collegiate female Cross-Country runners. We also assessed risk characteristics associated with each cluster.This randomly sampled population included 211 current National Collegiate Athletics Association (NCAA) Division I (DI) female cross country runners who completed a quantitative survey. We used latent class analysis (LCA) to group athletes into mutually exclusive classes based on shared response patterns of RED-S consequences. We computed descriptive statistics to identify demographics, personal characteristics, disordered eating and emotional health characteristics associated with each class.The average age of the sample was 21 years with mean body mass index 20.4 kg/m2. The LCA identified three unique classes of potential RED-S presentations: (1) low probability of RED-S consequences; (2) complex physical and psychological concerns with a higher burden of cardiovascular concern and (3) very high probability of anxiety with high burden of menstrual disturbance, bone injury and gastrointestinal concern. All classes were characterised by high levels of menstrual disturbance and distinguished by the number and burden of other potential RED-S consequences and in reported abuse history, emotional regulation and perfectionism.This study identified a high burden of menstrual disturbance in NCAA D1 cross country runners, and three unique presentations of RED-S consequences. Future research is warranted to better understand how early prevention and intervention strategies may mitigate RED-S consequences in distance runners.
Risk of major adverse cardiovascular events with tofacitinib versus tumour necrosis factor inhibitors in patients with rheumatoid arthritis with or without a history of atherosclerotic cardiovascular disease: a post hoc analysis from ORAL Surveillance
Authors: Christina Charles-Schoeman, Maya H Buch, Maxime Dougados, Deepak L Bhatt, Jon T Giles, Steven R Ytterberg, Gary G Koch, Ivana Vranic, Joseph Wu, Cunshan Wang, Kenneth Kwok, Sujatha Menon, Jose L Rivas, Arne Yndestad, Carol A Connell, Zoltan Szekanecz
Journal: Annals of the Rheumatic Diseases (2022)

Evaluate risk of major adverse cardiovascular events (MACE) with tofacitinib versus tumour necrosis factor inhibitors (TNFi) in patients with rheumatoid arthritis (RA) with or without a history of atherosclerotic cardiovascular disease (ASCVD) in ORAL Surveillance.
The On- and Off-Ramps of Oncology Accelerated Approval
Authors: Lola A. Fashoyin-Aje, Gautam U. Mehta, Julia A. Beaver, Richard Pazdur
Journal: New England Journal of Medicine (2022)

To address ongoing concerns about the implementation of the FDA's Accelerated Approval pathway in oncology, a comprehensive strategy is needed — one that equally emphasizes "on-ramp" and "off-ramp" considerations.
Trial of Antisense Oligonucleotide Tofersen for <i>SOD1</i> ALS
Authors: Timothy M Miller, Merit E Cudkowicz, Angela Genge, Pamela J Shaw, Gen Sobue, Robert C Bucelli, Adriano Chiò, Philip Van Damme, Albert C Ludolph, Jonathan D Glass, Jinsy A Andrews, Suma Babu, Michael Benatar, Christopher J McDermott, Thos Cochrane, Sowmya Chary, Sheena Chew, Han Zhu, Fan Wu, Ivan Nestorov, Danielle Graham, Peng Sun, Manjit McNeill, Laura Fanning, Toby A Ferguson, Stephanie Fradette
Journal: New England Journal of Medicine (2022)

The intrathecally administered antisense oligonucleotide tofersen reduces synthesis of the superoxide dismutase 1 (SOD1) protein and is being studied in patients with amyotrophic lateral sclerosis (ALS) associated with mutations in SOD1 (SOD1 ALS).
<i>Limosilactobacillus reuteri</i> DS0384 promotes intestinal epithelial maturation via the postbiotic effect in human intestinal organoids and infant mice
Authors: Hana Lee, Kwang Bo Jung, Ohman Kwon, Ye Seul Son, Eunho Choi, Won Dong Yu, Naeun Son, Jun Hyoung Jeon, Hana Jo, Haneol Yang, Yeong Rak Son, Chan-Seok Yun, Hyun-Soo Cho, Sang Kyu Kim, Dae-Soo Kim, Doo-Sang Park, Mi-Young Son
Journal: Gut Microbes (2022)

Little is known about the modulatory capacity of the microbiota in early intestinal development. We examined various intestinal models that respond to gut microbial metabolites based on human pluripotent stem cell-derived human intestinal organoids (hIOs): physiologically relevant in vitro fetal-like intestine, intestinal stem cell, and intestinal disease models. We found that a newly isolated Limosilactobacillus reuteri strain DS0384 accelerated maturation of the fetal intestine using 3D hIO with immature fetal characteristics. Comparative metabolomic profiling analysis revealed that the secreted metabolite N-carbamyl glutamic acid (NCG) is involved in the beneficial effect of DS0384 cell-free supernatants on the intestinal maturation of hIOs. Experiments in an intestinal stem cell spheroid model and hIO-based intestinal inflamed model revealed that the cell-free supernatant from DS0384 comprising NCG promoted intestinal stem cell proliferation and was important for intestinal protection against cytokine-induced intestinal epithelial injury. The probiotic properties of DS0384 were also evaluated, including acid and bile tolerance and ability to adhere to human intestinal cells. Seven-day oral administration of DS0384 and cell-free supernatant promoted the intestinal development of newborn mice. Moreover, NCG exerted a protective effect on experimental colitis in mice. These results suggest that DS0384 is a useful agent for probiotic applications and therapeutic treatment for disorders of early gut development and for preventing intestinal barrier dysfunction.
Case 29-2022: A 33-Year-Old Man with Chronic Diarrhea and Autoimmune Enteropathy
Authors: Francis P. Colizzo, Stuti G. Shroff, Frances A. High, Yi-Bin Chen, Sara Barmettler
Journal: New England Journal of Medicine (2022)

A 33-year-old man was evaluated for relapsing diarrhea, which had initially developed during infancy. Autoimmune enteropathy had been diagnosed, but symptoms recurred despite treatment. A diagnostic test was performed.
Correction To: KLF6 facilitates differentiation of odontoblasts through modulating the expression of P21 in vitro
Authors: Zhuo Chen, Wenzhi Wu, Chen Zheng, Yanhua Lan, Huizhi Xie, Zhijian Xie
Journal: International Journal of Oral Science (2022)

The third section of RESULTS: Effects of Klf6 overexpression on gene expression, proliferation, apoptosis, and cell cycle.Paragraph 4: The Klf6 overexpression group had a lower average proportion of G0/G1 phase cells (52.77% ± 2.25%) (P < 0.05).In the control group, that proportion was 62.07% ± 2.95%.Furthermore, 35.62% ± 1.95% and 25.91% ± 1.17% of the cells in the Klf6 overexpression and control groups were in the S phase, respectively (P < 0.05).The G2/M phase proportions were 11.63% ± 0.30% and 12.53% ± 1.29% for the Klf6 overexpression and control groups, respectively (P > 0.05).Corrected to: The control group had a lower average proportion of G0/G1 phase cells (52.77% ± 2.25%) (P < 0.05).In the Klf6 overexpression group, that proportion was 62.07% ± 2.95%.Furthermore, 35.62% ± 1.95% and 25.91% ± 1.17% of the cells in the control and Klf6 overexpression groups were in the S phase, respectively (P < 0.05).The G2/M phase proportions were 11.63% ± 0.30% and 12.53% ± 1.29% for the control and Klf6 overexpression groups, respectively (P > 0.05).